0steoarthritis (OA) is a progressive, degenerative, and debilitating musculoskeletal disorder that afflicts more that 35% of the US population above 45 years of age. Its adverse effects on the quality of life for millions of elderly, the costs of health care, and loss of economic productivity, make it a major health problem. Management of OA and associated pain is a challenge. Current pharmacologic therapies only provide temporary relief and have severe side effects. Surgical interventions are useful only in advanced cases of OA. Therefore, new interventions to inhibit progression of this disease are urgently needed. A body of evidence suggests that, well designed regular exercise is beneficial to joints afflicted with OA. However, the amounts and types o exercises that are beneficial and not destructive to OA joints are as yet unknown. It is our hypothesis that low to moderate levels of exercise are beneficial/reparative to damaged joints because it inhibits inflammation and induces synthesis of matrix proteins. This is based on our recent in vitro findings that, mechanical strain (MS) o low magnitude (but not of high magnitude) acts as a potent antagonist of proinflammatory cytokine actions in chondrocytes. For example, MS suppresses transcription of mRNA and synthesis of multiple proinflammatory proteins, such as iNOS, COX-2, MMP-l, MMP-3, IL-1B IL-6, all of which are expressed during cartilage destruction in OA. Furthermore, MS induces synthesis of tissue inhibitor of metalloproteases (TIMPs), proteoglycans, and collagen type 11, all of which are involved in cartilage repair. Given that the level of MS critically regulates the proinflammatory response of chondrocytes, it is important to determine the precise amount of MS necessary for therapeutic effectiveness of exercise. Therefore, our goal is to evaluate parameters for exercise-based therapies, that can limit or prevent the progression of OA. Specifically, we will examine the molecular responses of chondrocytes and synovial cells to exercise regimens of varying intensity, duration, and range of motion, in order to determine the level of exercise needed to induce appropriate biomechanical signals that will suppress inflammation and initiate repair of OA joints. The evaluation of exercise regimens based on the molecular actions of MS will provide: (i) molecular basis for the efficacy of exercise in treating damaged/inflamed joints; (ii) parameters for safe application of physical therapies to accelerate cartilage repair; and (iii) guidelines and endpoints for optimal therapeutic use of exercise in human OA.